Abstract The opioid crisis in North America comes with a multitude of health consequences, including HIV and Hepatitis C (HCV) outbreaks. HIV and HCV are major contributors to morbidity and mortality among persons who inject drugs (PWID). These infections also bear significant medical costs. While HIV treatment scale-up remains essential, significant improvements in HIV and HCV prevention and care are required to reduce substantially the HIV and HCV burden among PWID. Pre-exposure prophylaxis (PrEP) and the HCV cure regimens have transformative potential to reduce these two co-occurring epidemics. A key question for implementation research is how to best integrate these pharmacological advances in prevention and care strategies for PWID. Given the relative dearth of prior research on PrEP among PWID, we critically need to expand our understanding of the potential role of PrEP for PWID engaged in HCV assessment and treatment. Within this context, we propose a randomized hybrid effectiveness-implementation trial (n=500) to evaluate two implementation strategies for PrEP and HCV care integration among PWID: on-site integrated care (PrEP initiation and HCV treatment) vs. off-site referral with patient navigation to specialized care. HIV-negative PWID will be recruited from two venues?opioid substitution therapy (OST) venues and syringe exchange programs (SEPs)?within two North American cities?Miami and Montral. The cities provide variability in background health access (Montreal-High Services/Low Barriers versus Miami-Low Services/High Barriers); venues provide variability in overhead/resources (OTPs-High Resources versus SEPs-Low Resource). There are two overall aims: 1) To determine if integrated PrEP and HCV treatment offered on-site in treatment and harm reduction settings results in higher rates of a) sustained PrEP adherence and/or b) HCV cure (primary outcomes), compared to an off-site referral with patient navigation, and to c) test the contributions of local environment and venue on primary outcomes, and 2) To evaluate a) the health care utilization impact and the relative resource use of the on-site integrated care approach compared to the referral with patient navigator approach and b) the health care resources required to scale up these intervention approaches in the local environments and settings. Secondary outcomes will include PrEP initiation, use, long-term sustained PrEP adherence, HCV treatment initiation, risk behavior changes, HCV infection/reinfection, and STD/HIV incidence. For these secondary outcomes, we also will include a qualitative study to understand the interplay of the personal, interpersonal, and social contextual factors that may be associated with PrEP adherence and issues of behavioral compensation over time for PWID. Additional qualitative study will examine facilitators and barriers to implementation. This two-city by two-venue design will provide crucial information to understand implementation/dissemination issues in both high and low resource geographic contexts and high and low overhead venues.